HIV-1 infection of CD4 T cells leads to cytopathic effects and cell demise, which is counter to the observation that certain HIV-1-infected cells possess a remarkable long-term stability and can persist lifelong in infected individuals treated with suppressive antiretroviral therapy (ART). Using quantitative mass spectrometry-based proteomics, we showed that HIV-1 infection activated cellular survival programs that were governed by BIRC5, a molecular inhibitor of cell apoptosis that is frequently overexpressed in malignant cells. BIRC5 and its upstream regulator OX40 were upregulated in productively and latently infected CD4 T cells and were functionally involved in maintaining their viability. Moreover, OX40-expressing CD4 T cells from ART-treated patients were enriched for clonally expanded HIV-1 sequences, and pharmacological inhibition of BIRC5 resulted in a selective decrease of HIV-1-infected cells in vitro. Together, these findings suggest that BIRC5 supports long-term survival of HIV-1-infected cells and may lead to clinical strategies to reduce persisting viral reservoirs.

The ability to persist long term in latently infected CD4 T cells represents a characteristic feature of HIV-1 infection and the predominant barrier to efforts aiming at viral eradication and cure. Yet, increasing evidence suggests that only small subsets of CD4 T cells with specific developmental and maturational profiles are able to effectively support HIV-1 long-term persistence. Here, we analyzed how the functional polarization of CD4 T cells shapes and structures the reservoirs of HIV-1-infected cells. We found that CD4 T cells enriched for a Th1/17 polarization had elevated susceptibilities to HIV-1 infection in ex vivo assays, harbored high levels of HIV-1 DNA in persons treated with antiretroviral therapy, and made a disproportionately increased contribution to the viral reservoir relative to their contribution to the CD4 T memory cell pool. Moreover, HIV-1 DNA levels in Th1/17 cells remained stable over many years of antiretroviral therapy, resulting in a progressively increasing contribution of these cells to the viral reservoir, and phylogenetic studies suggested preferential long-term persistence of identical viral sequences during prolonged antiretroviral treatment in this cell compartment. Together, these data suggest that Th1/17 CD4 T cells represent a preferred site for HIV-1 DNA long-term persistence in patients receiving antiretroviral therapy. A lthough antiretroviral therapy (ART) is highly effective in suppressing HIV-1 replication and clinical HIV-1 disease manifestations, small reservoirs of HIV-1-infected cells persist despite treatment and can lead to rapid viral rebound once treatment is stopped (1, 2). Identifying the functional and phenotypic characteristics of cell subsets that harbor replication-competent virus during suppressive antiretroviral therapy is a critical step for developing interventional strategies to target residual viral reservoirs. Most available evidence supports the notion that latently infected CD4 T cells containing chromosomally integrated but transcriptionally silent HIV-1 DNA represent the most dominant cell population responsible for HIV persistence despite treatment (3-5). However, it is increasingly recognized that such cells represent a phenotypically diverse cell population that consists of a variety of different cell subsets with distinct developmental profiles and functional properties (6-10), divergent levels of permissiveness to HIV-1 infection and latency, and, most likely, different susceptibilities to clinical strategies or pharmaceutical agents aiming at reversing viral latency and inducing HIV-1 eradication.From a developmental perspective, memory CD4 T cell evolution can be described as a hierarchical process during which immature, long-lived cells undergo progressive commitment to more differentiated cell types (11). Recent data suggest that the initial, most immature population of memory CD4 T cells consists of a small number of extremely long-lasting cells that phenotypically express a mix of naive and memory cell markers and display ...

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